Free Drug Counterparts Research Articles

The anticancer potential of tetrahydrocurcumin-phytosomes against oral carcinoma progression

BackgroundHerbal medicine combined with nanotechnology offers an alternative to the increasing burden of surgery and/or chemotherapy, the main therapeutics of oral carcinoma. Phytosomes are nano-vesicular systems formed by the interaction between phospholipids and phyto-active components via hydrogen bonding, exhibiting superior efficacy over pure phytocomponents in drug delivery.MethodsTetrahydrocurcumin (THC)-phytosomes were prepared by thin film hydration method. After characterization, in vitro cytotoxicity, antiproliferative capacity, antioxidant potential and full apoptotic workup were paneled on oral squamous cell carcinoma (SCC4) in comparison with native THC-solution and cisplatin (3.58 µg/mL intravenous injection), as positive controls. In addition, we tested the three medications on normal oral keratinocytes and gingival fibroblasts to attest to their tissue-selectivity.ResultsSuccessful preparation of THC-phytosomes using 1:1 molar ratio of THC to phospholipid exhibited significantly increased aqueous solubility, good colloidal properties, and complete drug release after one hour. On SCC4 cells, THC-phytosomes, at their dose-/time-dependency at ~ 60.06 µg/mL escalated cell percentages in the S-phase with 32.5 ± 6.22% increase, as well as a startling 29.69 ± 2.3% increase in apoptotic population. Depletion of the cell colonies survival to 0.29 ± 0.1% together with restraining the migratory rate by -6.4 ± 6.8% validated THC-phytosomes’ antiproliferative capacity. Comparatively, the corresponding results of THC-solution and cisplatin revealed 12.9 ± 0.9% and 25.8 ± 1.1% for apoptosis and 0.9 ± 0.1% and 0.7 ± 0.08% for colony survival fraction, respectively. Furthermore, the nanoformulation exhibited the strongest immuno-positivity to caspase-3, which positively correlated with intense mitochondrial fluorescence by Mitotracker Red, suggesting its implication in the mitochondrial pathway of apoptosis, a finding further explained by the enormously high Bax and caspase-8 expression by RT-qPCR. Finally, the THC groups showed the lowest oxidative stress index, marking their highest free radical-scavenging potential among the test groups.ConclusionsTHC-phytosomes are depicted to be an efficient nanoformulation that enhanced the anticancer efficacy over the free drug counterpart and the conventional chemotherapeutic. Additionally, being selective to cancer cells and less cytotoxic to normal cells makes THC-phytosomes a potential candidate for tissue-targeted therapy.

Abstract 134: Lesion-specific Suppression Of YAP/TAZ By Biomimetic Nanoparticles Ameliorates Atherosclerosis

Introduction: Recent evidence highlights the potential therapeutic benefit of targeting YAP/TAZ in mitigating atherosclerosis. However, challenges associated with systemic delivery hinder the translation of the mechanistic discovery into an effective treatment. This study aimed to address the challenges by developing a lesion-specific nanodrug to achieve site-specific inhibition of YAP/TAZ for atherosclerosis therapy. Hypothesis: We have formulated a novel monocyte membrane-coated nanoparticle (MoNP) platform designed to facilitate precise delivery of payloads to atherosclerotic arteries. Our hypothesis is that leveraging MoNP for the targeted delivery of verteporfin (VP), a potent YAP/TAZ inhibitor, will significantly enhance the efficacy in mitigating atherosclerosis. Methods: Polymeric nanoparticles containing VP were prepared using an emulsion approach, followed by enclosing them with plasma membranes isolated from monocytes, yielding MoNP-VP. The pharmacological effects of MoNP-VP were assessed on cultured vascular and immune cells, as well as in the atherosclerotic mouse model. Results: Our in vivo findings demonstrated that the administration of MoNP-VP, as opposed to free VP, led to a substantial reduction in arterial inflammation and plaque development, suggesting that VP delivered by MoNP is a more effective route than its free drug counterpart. To dissect the mechanisms of actions, we analyzed the arterial tissues post-treatment using scRNA-seq analysis. Our results identified 9 distinct cell clusters within the affected arteries. Specifically, MoNP-VP treatment led to a decrease in macrophage (MΦ) clusters and an increase in the cluster of smooth muscle cells (SMC). Furthermore, our in vitro assays confirmed the efficacies of MoNP-VP in reducing the atheroprone phenotypes. These include diminished endothelial cell activation, less proliferation and migration of SMC, and a reduction in foam cell formation from MΦ. Conclusion: Together, these findings support the notion that targeting YAP/TAZ dysregulation is a feasible strategy for reducing plaque development and progression and demonstrate that MoNP-VP is a highly effective nanodrug for treating atherosclerosis.

Abstract 4058: Nanoparticle delivery of interleukin-2 induces anti-tumor immune response and therapeutic efficacy in mouse tumor models

Abstract Immune checkpoint inhibitors (ICIs) have demonstrated robust responses in some solid tumor types. However, the low response rate, which is associated with lack of pre-existing tumor-infiltrating lymphocytes (TILs), remains a significant challenge. Interleukin-2 (IL-2) can effectively expand TILs and has been FDA-approved for metastatic renal cancer and melanoma. However, IL-2 has several drawbacks—including short circulation half-life, dose-limiting toxicities, and counterproductive activation of regulatory T cells (Tregs)—resulting in less than 10% complete response rate. Numerous efforts have been made to enhance IL-2 formulations, but none have yet received FDA approval. In this study, we utilized our proprietary nanoparticle platform (Pdx-NP™) to improve IL-2 formulation. Pdx-NP™ can load IL-2 with near-complete binding, resulting in a 160-nm nanoconstruct (IL2-NP), suitable for both local and intravenous administrations. To evaluate the efficacy, we utilized bilateral melanoma (B16F10) and colon (MC38) tumor models, in which the local tumor was treated intratumorally for 3 doses and the distal tumor was left untreated to assess the systemic anti-tumor immune response. In the B16F10 model, IL2-NP treatment demonstrated favorable immune profiles in local and distal tumors and the draining lymph nodes, such as increased CD8+ T cell proliferation, CD8+ T cells/Treg ratio, and recruitment of dendritic cells and macrophages, compared to saline or free IL-2 counterparts. These positive immune responses translated into significant growth reduction of IL2-NP treated tumors and improvement in survival of the mice compared to free IL-2. In the MC38 tumor model, the IL2-NP treatment resulted in complete regression of both local and distal tumors in 43% of the mice. When combined with ICIs (αPD-1 and αCTLA-4), the treatment achieved a cure rate of 100%, whereas ICIs alone yielded only a 29% cure rate. In conclusion, IL2-NP induces robust proliferation and activation of TILs and is efficacious both as a monotherapy and in combination with ICIs. This is due to the ability of Pdx-NP™ to protect and retain therapeutics within tumors, with an 8-fold increase in tumor accumulation over the free drug counterpart. Our ongoing efforts are focused on the targeted delivery of IL-2 to tumors upon systemic administration, using αPD-L1 antibody-conjugated Pdx-NP™. This antibody-conjugated nanoparticle has an elimination half-life (t1/2) of about 25 hrs in non-human primates. Paired with αPD-L1 for tumor homing, this nanoconstruct is hypothesized to enhance IL-2 accumulation in tumors compared to free IL-2, which has t1/2 of only 1.5 hrs in human. The current clinical landscape of cancer immunotherapy focuses on combinational approaches, and our versatile Pdx-NP™ platform, which is capable of co-delivering different classes of therapeutics, is well suited for this endeavor. Citation Format: Ruijie Wang, Alyssa Wallstrum, Natalie White, Pramod Kumar, Tongchatra Watcharawittayakul, Noah A. Crumrine, Cole Baker, Jeremy Saito, Moataz Reda, Worapol Ngamcherdtrakul, Wassana Yantasee. Nanoparticle delivery of interleukin-2 induces anti-tumor immune response and therapeutic efficacy in mouse tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4058.

Lower cardiotoxicity of CPX-351 relative to daunorubicin plus cytarabine free-drug combination in hiPSC-derived cardiomyocytes in vitro

Liposomal formulations are hypothesized to alleviate anthracycline cardiotoxicity, although this has only been documented clinically for doxorubicin. We developed an in vitro multiparametric model using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) to assess the relative toxicity of anthracyclines across formulations. Proof of concept was established by treating hiPSC-CM with equivalent concentrations of free and liposomal doxorubicin. The study was then repeated with free daunorubicin plus cytarabine and CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine. hiPSC-CM were treated with free-drug or liposomal formulations for 24 h on Days 1, 3, and 5 at equivalent concentrations ranging from 0 to 1000 ng/mL and assessed on subsequent days. Free-drug treatment resulted in concentration-dependent cumulative cytotoxicity (microscopy), more profound decrease in ATP levels, and significant time- and concentration-dependent decreases in oxygen consumption versus liposomal formulations (p < 0.01). Repeated free-drug exposure also resulted in greater release of biomarkers (cardiac troponin I, FABP3) and lactate dehydrogenase, as well as in a biphasic rhythmicity response (initial increase followed by slowing/quiescence of beating) indicating significant injury, which was not observed after repeated exposure to liposomal formulations. Overall, liposomal formulations were considerably less toxic to hiPSC-CM than their free-drug counterparts. Clinical data will be needed to confirm findings for CPX-351.

Niosomal Delivery of Celecoxib and Metformin for Targeted Breast Cancer Treatment.

Breast cancer continues to be a prominent worldwide health concern and requires continued investigation into innovative therapeutic approaches. Here, we report the first investigation into the therapeutic efficacy of combining Metformin (MET) and Celecoxib (CXB), both in free and niosomal form, for the treatment of breast cancer. Our investigation encompassed the characterization of these niosomal drug carriers, their stability assessment, and their effect on breast cancer cell models. The thin-film hydration technique was employed to prepare niosomes with spherical, uniform-size distributions and high encapsulation efficiencies. The niosomes were characterized by TEM, particle size analyzer, and ATR-FTIR. The niosomes with an average size of 110.6 ± 0.6 and 96.7 ± 0.7, respectively, for MET and CXB were stable when stored at 4 °C for three months with minimal drug leakage, minor changes in encapsulation efficiency and size, and unchanged physicochemical parameters. Evaluation in two-dimensional (2D) and three-dimensional (3D) viability assays demonstrated an increased cytotoxicity of encapsulated drugs when compared to their free-drug counterparts. Additionally, the combination of Metformin Niosomal Particles (MET NPs) and Celecoxib Niosomal Particles (CXB NPs) led to decreased cell viability in both 2D and 3D models compared to each drug administered individually. When comparing the effect of the niosomal versus the free combination of the drugs on cell migration, we found that both interventions effectively prevented cell migration. However, the efficacy of the niosomes' combination was not superior to that of the free drug combination (p < 0.05). In conclusion, the results of this study provide valuable insights into the potential application of combining MET and CXB nanoparticle delivery systems to breast cancer treatment. Exploring the in vivo application of this drug delivery system could open new avenues for more effective and targeted therapeutic approaches for breast cancer patients.

Amygdalin-folic acid-nanoparticles inhibit the proliferation of breast cancer and enhance the effect of radiotherapy through the modulation of tumor-promoting factors/ immunosuppressive modulators in vitro

IntroductionBreast cancer (BC) cells often develop multiple mechanisms of chemo- and radio-resistance during tumor progression, which is the major reason for the failure of breast cancer therapy. Targeted nanomedicines have tremendous therapeutic potential in BC treatment over their free drug counterparts. Searching for chemo- and radio-sensitizers to overcome such resistance is therefore urgently required. The goal of this study is to evaluate and compare the radio-sensitizer efficacy of amygdalin-folic acid nanoparticles (Amy-F) on MCF-7 and MDA-MB-231 cells.Materials and methodsThe effects of Amy-F on MCF-7 and MDA-MB-231 cell proliferation and IC50 were assessed using MTT assay. The expression of proteins involved in several mechanisms induced by Amy-F in MCF-7 and MDA-MB-231 cells, including growth inhibition, apoptosis, tumor growth regulators, immuno-modulators, and radio-sensitizing activities were evaluated via flow cytometry and ELISA assay.ResultsNanoparticles demonstrated sustained Amy-F release properties and apparent selectivity towards BC cells. Cell-based assays revealed that Amy-F markedly suppresses cancer cell growth and improves radiotherapy (RT) through inducing cell cycle arrest (G1 and sub-G1), and increases apoptosis as well as reduces the proliferation of BC by down-regulating mitogen-activated protein kinases (MAPK/P38), iron level (Fe), nitric oxide (NO), and up-regulating the reactive oxygen species level (ROS). Amy-F has also been shown to suppress the expression of the cluster of differentiation (CD4 and CD80), and interfere with the Transforming growth factor beta (TGF- β)/Interferon-gamma (INF-g)/Interleukin-2 (IL-2)/Interleukin-6 (IL-6)/Vascular endothelial growth factor (VEGF) induced suppression in its signaling hub, while up-regulating natural killer group 2D receptor (NKG2D) and CD8 expression.ConclusionsCollectively, the novel Amy-F either alone or in combination with RT abrogated BC proliferation.

Design and Characterization of a Novel Venetoclax-Zanubrutinib Nano-Combination for Enhancing Leukemic Cell Uptake and Long-Acting Plasma Exposure

Leukemia remains incurable partly due to difficulties in reaching and maintaining therapeutic drug concentrations in the target tissues and cells. Next-generation drugs targeted to multiple cell checkpoints, including the orally active venetoclax (Bcl-2 target) and zanubrutinib (BTK target), are effective and have improved safety and tolerability compared to conventional, nontargeted chemotherapies. However, dosing with a single agent frequently leads to drug resistance; asynchronous coverage due to the peak-and-trough time-course of two or more oral drugs has prevented drug combinations from simultaneously knocking out the respective drugs' targets for sustained leukemia suppression. Higher doses of the drugs may potentially overcome asynchronous drug exposure in leukemic cells by saturating target occupancy, but higher doses often cause dose-limiting toxicities. To synchronize multiple drug target knockout, we have developed and characterized a drug combination nanoparticle (DcNP), which enables the transformation of two short-acting, orally active leukemic drugs, venetoclax and zanubrutinib, into long-acting nanoformulations (VZ-DCNPs). VZ-DCNPs exhibit synchronized and enhanced cell uptake and plasma exposure of both venetoclax and zanubrutinib. Both drugs are stabilized by lipid excipients to produce the VZ-DcNP nanoparticulate (d ~ 40 nm) product in suspension. The VZ-DcNP formulation has enhanced uptake of the two drugs (VZ) in immortalized leukemic cells (HL-60), threefold over that of its free drug counterpart. Additionally, drug-target selectivity of VZ was noted with MOLT-4 and K562 cells that overexpress each target. When given subcutaneously to mice, the half-lives of venetoclax and zanubrutinib were extended by approximately 43- and 5-fold, respectively, compared to an equivalent free VZ. Collectively, these data suggest that VZ in VZ-DcNP warrant consideration for preclinical and clinical development as a synchronized and long-acting drug-combination for the treatment of leukemia.

An in-vitro quantitative investigation on the synergistic effect of capsaicin and 5-fluorouracil encapsulated into lipid nanocapsules to treat breast cancer

Background Breast cancer conventional therapeutics are effective; however, they encounter some limitations including multidrug resistance, the presence of pharmacological barriers, and non-selectivity which hinder their optimal therapeutic efficacy. Aim Overcoming such drawbacks necessitates the development of efficient drug vehicles including lipid-based nanoparticles. This study aimed to quantitatively investigate in-vitro the synergistic therapeutic effect of the novel combination of capsaicin and 5-fluorouracil (5-FU) encapsulated in lipid nanocapsules (LNCs). Method To this end, thorough physicochemical and in-vitro assessments on the breast cancer cell line (MCF-7) were done. The drug-loaded LNCs were characterized using DLS, TEM imaging, stability study, and in-vitro release study. Furthermore, the biological activity of the prepared LNCs was assessed by implementing comparative cytotoxicity studies as well as apoptosis, and cell cycle flow cytometric analyses. Results The developed nanoformulations were monodisperse with average particle size (PS) of 31, 43.8, and 127.3 nm for empty LNCs, Cap-LNCs, and 5-FU-LNCs, respectively, and with a surface charge of −35.4, −21.7 and −31.4 mV, respectively, reflecting good physical stability. The TEM micrographs revealed the spherical morphology of the drugs-loaded LNCs with comparable PS to that obtained by DLS. on the other hand, all the biological assessments confirmed the superior antiproliferative effect of the combined drug-loaded LNCs over their free drug counterparts. Conclusion Intriguingly, the study findings highlighted the potential synergistic activity of the drugs (capsaicin and 5-FU) and the extensive enhancement of their biological activity through incorporation into LNCs. Such promising results will pave the way to further novel combined nanoformulation in preclinical and clinical studies on breast cancer patients.

Dual Drug Loaded Nanotheranostic Platforms as a Novel Synergistic Approach to Improve Pancreatic Cancer Treatment

AbstractThis study focuses on the development of theranostic, dual drug‐loaded nanocarriers to propose a proof‐of‐principle therapeutic approach in the treatment of pancreatic ductal adenocarcinoma (PDAC). The nanoconstructs consist of a core of zinc oxide nanocrystals doped with gadolinium, useful as a potential contrast agent in magnetic resonance imaging applications. After functionalizing their surface with amino‐propyl groups, the physical adsorption of two hydrophobic drugs is performed: Vismodegib and Sorafenib. Their synergistic use might improve PDAC treatment and stroma depletion when co‐delivered in the tumor microenvironment for future in vivo applications. To enhance the nanoconstructs’ biostability, the ensemble is coated by a lipid bilayer and a tumor targeting peptide is incorporated on the outer shell surface. As a first proof of concept, the resulting nanoconstructs are tested against two pancreatic cancer cell lines, showing a modest increase in treatment efficacy compared to the free drug counterparts and proving to spare healthy pancreatic cells. In a second testing set, the dual‐drug loaded nanoconstructs are tested on both cell lines previously sensitized to a first‐line chemotherapeutic drug, Gemcitabine, showing an improved treatment response. From these preliminary results, the nanotheranostic platforms might constitute a good starting point for future PDAC therapy and diagnosis studies.

FA-HA-Amygdalin@Fe2O3 and/or γ-Rays Affecting SIRT1 Regulation of YAP/TAZ-p53 Signaling and Modulates Tumorigenicity of MDA-MB231 or MCF-7 Cancer Cells.

Breast cancer (BC) has a complex and heterogeneous etiology, and the emergence of resistance to conventional chemo-and radiotherapy results in unsatisfactory outcomes during BC treatment. Targeted nanomedicines have tremendous therapeutic potential in BC treatment over their free drug counterparts. Hence, this study aimed to evaluate the newly fabricated pH-sensitive multifunctional FAHA- Amygdalin@Fe2O3 nano-core-shell composite (AF nanocomposite) and/or γ-radiation for effective localized BC therapy. The physicochemical properties of nanoparticles were examined, including stability, selectivity, responsive release to pH, cellular uptake, and anticancer efficacy. MCF-7 and MDA-MB-231 cells were treated with AF at the determined IC50 doses and/or exposed to γ-irradiation (RT) or were kept untreated as controls. The antitumor efficacy of AF was proposed via assessing anti-proliferative effects, cell cycle distribution, apoptosis, and determination of the oncogenic effectors. In a bio-relevant medium, AF nanoparticles demonstrated extended-release characteristics that were amenable to acidic pH and showed apparent selectivity towards BC cells. The bioassays revealed that the HA and FA-functionalized AF markedly hindered cancer cell growth and enhanced radiotherapy (RT) through inducing cell cycle arrest (pre-G1 and G2/M) and increasing apoptosis, as well as reducing the tumorigenicity of BCs by inhibiting Silent information regulation factor 1 (SIRT1) and restoring p53 expression, deactivating the Yes-associated protein (YAP)/ Transcriptional coactivator with PDZ-binding motif (TAZ) signaling axis, and interfering with the tumor growth factor- β(TGF- β)/SMAD3 and HIF-1α/VEGF signaling hub while up-regulating SMAD7 protein expression. Collectively, the novel AF alone or prior RT abrogated BC tumorigenicity.

Molecular bottlebrush prodrugs as mono- and triplex combination therapies for multiple myeloma.

Cancer therapies often have narrow therapeutic indexes and involve potentially suboptimal combinations due to the dissimilar physical properties of drug molecules. Nanomedicine platforms could address these challenges, but it remains unclear whether synergistic free-drug ratios translate to nanocarriers and whether nanocarriers with multiple drugs outperform mixtures of single-drug nanocarriers at the same dose. Here we report a bottlebrush prodrug (BPD) platform designed to answer these questions in the context of multiple myeloma therapy. We show that proteasome inhibitor (bortezomib)-based BPD monotherapy slows tumour progression in vivo and that mixtures of bortezomib, pomalidomide and dexamethasone BPDs exhibit in vitro synergistic, additive or antagonistic patterns distinct from their corresponding free-drug counterparts. BPDs carrying a statistical mixture of three drugs in a synergistic ratio outperform the free-drug combination at the same ratio as well as a mixture of single-drug BPDs in the same ratio. Our results address unanswered questions in the field of nanomedicine, offering design principles for combination nanomedicines and strategies for improving current front-line monotherapies and combination therapies for multiple myeloma.

Galactosed and Reduction-Responsive Nanoparticles Assembled from Trimethylchitosan-Camptothecin Conjugates for Enhanced Hepatocellular Carcinoma Therapy.

The targeted delivery of drugs to tumor cells and prevention of premature release before reaching the target is one of the key challenges to developing nanomedicines. In this paper, galactose decorated trimethyl chitosan (GT)–camptothecin (CPT) prodrug nanoparticles (GT-ss-CPT NPs) were prepared from GT-CPT conjugates linked by dithiodipropionic acid. The obtained GT-ss-CPT NPs were spherical with a particle size of 184.1 nm. GT-ss-CPT NPs displayed low drug release under physiological conditions, whereas efficient drug release was triggered by high GSH concentration. GT-ss-CPT NPs exhibited a higher antitumor effect both in vitro and in vivo than the free drug counterpart. More importantly, GT-ss-CPT NPs reduced the high systematic toxicity of CPT to tumor-bearing mice. In summary, GT-ss-CPT NPs can not only inhibit the premature release of CPT but also have a great potential for targeted hepatocellular carcinoma chemotherapy.

Stealth doxorubicin conjugated bimetallic selenium/silver nanoparticles for targeted cervical cancer therapy

Bimetallic nanosized delivery systems are attracting a lot of research interest as alternatives to monometallic delivery systems. This study evaluated the ability of bimetallic selenium silver chitosan pegylated folic acid targeted nanoparticles (SeAgChPEGFA NPs) to deliver doxorubicin (DOX) in cervical cancer cells. Comparison studies using monometallic selenium chitosan pegylated folic acid (SeChPEGFA NPs) targeted NPs and free DOX were also conducted. The prepared NPs and their drug nanocomplexes were characterised morphologically and physico-chemically. Drug binding and releasing studies were conducted under a simulated environment in vitro. The cytotoxicity and apoptosis studies were studied using the 3-[(4, 5-dimethylthiazol-2-yl)−2, 5-diphenyl tetrazolium bromide] (MTT) assay and the dual dye staining. The findings revealed that the bimetallic SeAgChPEGFA NPs displayed better colloidal stability, superior physico-chemical qualities, and higher binding abilities in comparison with monometallic SeChPEGFA NPs. In addition, the SeAgChPEGFA NPs showed the pH-triggered controlled drug release and cell-specific cytotoxicity. These findings suggest that the bimetallic NPs are superior delivery systems when compared to their monometallic NPs and free drug counterparts, thus, setting a platform for further in vivo examination.

Cancer Nanomedicine and Immune System—Interactions and Challenges

Nanoparticles have tremendous therapeutic potential in the treatment of cancer as they increase drug delivery, attenuate drug toxicity, and protect drugs from rapid clearance. Since Doxil®, the first FDA-approved nanomedicine, several other cancer nanomedicines have been approved and have successfully increased the efficacy over their free drug counterparts. Although their mechanisms of action are well established, their effects towards our immune system, particularly in the tumor microenvironment (TME), still warrant further investigation. Herein, we review the interactions between an approved cancer nanomedicine with TME immunology. We also discuss the challenges that need to be addressed for the full clinical potential of ongoing cancer nanomedicines despite the encouraging preclinical data.

Nanoliposomes as Multidrug Carrier of Gemcitabine/Paclitaxel for the Effective Treatment of Metastatic Breast Cancer Disease: A Comparison with Gemzar and Taxol

AbstractSeveral liposomal drugs have received clinical approval for the treatment of cancer due to the reduced side effects and/or improved therapeutic efficacy in comparison to their respective free drug counterparts. In this study, nanoliposomes are designed as multidrug carriers for codelivering gemcitabine hydrochloride (Gemzar) and paclitaxel (Taxol) and evaluating their anticancer activity in several triple negative human breast cancer cell lines and in a mouse model of metastatic breast cancer. The results demonstrate that the nanoliposomes significantly decrease the cell viability of breast cancer cells compared to combination treatment with the free drugs. Furthermore, the chemotherapeutics coloaded nanoliposomes dramatically decrease the tumor growth and improve survival times, while combination treatment with Gemzar and Taxol has a modest effect on cancer progression. Moreover, pharmacokinetic analysis demonstrates that nanoliposomes increase the half‐life of gemcitabine hydrochloride and paclitaxel 6.3‐fold and 1.7‐fold, respectively. Taken together, the findings indicate that gemcitabine hydrochloride and paclitaxel‐coloaded nanoliposomes can provide an effective treatment strategy for metastatic breast cancer.

Combination of Curcumin and Paclitaxel Liposomes Exhibits Enhanced Cytotoxicity Towards A549/A549-T Cells and Unaltered Pharmacokinetics.

Background: Combination chemotherapy of chemo-drugs and natural herbal drugs has been shown to be more advantageous than individual treatment with respect to enhancing cytotoxicity, alleviating toxicity and controlling the development of multidrug resistance (MDR). Purpose: The goal of this study is to construct a combined drug delivery system of curcumin liposomes (CUR-LPs) and paclitaxel liposomes (PTX-LPs) to enhance the anticancer activity and reverse the MDR of PTX. Methods: CUR-LPs and PTX-LPs were prepared by solvent evaporation method with optimal formulation composition. MTT assay was used to assess the effect of the combination of CUR-LPs and PTX-LPs treatments on the proliferation of A549/A549-T cells. In addition, the pharmacokinetic behaviors of the combination treatments were evaluated by HPLC. Results : The mixed liposomes were found to have negative zeta-potential (-17.91 ± 1.21 mV) and relatively uniform particle size (105.88 ± 3.19 nm) with a low polydispersity index (0.21 ± 0.016). IC50 of PTX for combination of CUR-LPs and PTX-LPs decreased in the range of 1.47-2.9 times and 1.59-2.5 times compared to the free-drug counterparts in A549 and A549-T cells, respectively. Superior cytotoxicity and higher synergy (CI< 0.4) were observed for the combination treatment with ratio of 40:1 (CUR-LPs:PTX-LPs) compared with the free-drug counterparts in both cell lines tested. Following intravenous administration in rats, liposomes presented higher bioavailability (CUR-LPs: 9.02 fold; PTX-LPs: 7.32 fold) compared to free drugs. Co-administration did not alter the respective pharmacokinetic behaviors. Conclusion: Overall, the present study presents a promising strategy for the development of compound formulations of CUR and PTX.

Extracellular vesicles derived from Plasmodium-infected and non-infected red blood cells as targeted drug delivery vehicles.

Among several factors behind drug resistance evolution in malaria is the challenge of administering overall doses that are not toxic for the patient but that, locally, are sufficiently high to rapidly kill the parasites. Thus, a crucial antimalarial strategy is the development of drug delivery systems capable of targeting antimalarial compounds to Plasmodium with high specificity. In the present study, extracellular vesicles (EVs) have been evaluated as a drug delivery system for the treatment of malaria. EVs derived from naive red blood cells (RBCs) and from Plasmodium falciparum-infected RBCs (pRBCs) were isolated by ultrafiltration followed by size exclusion chromatography. Lipidomic characterization showed that there were no significant qualitative differences between the lipidomic profiles of pRBC-derived EVs (pRBC-EVs) and RBC-derived EVs (RBC-EVs). Both EVs were taken up by RBCs and pRBCs, although pRBC-EVs were more efficiently internalized than RBC-EVs, which suggested their potential use as drug delivery vehicles for these cells. When loaded into pRBC-EVs, the antimalarial drugs atovaquone and tafenoquine inhibited in vitro P. falciparum growth more efficiently than their free drug counterparts, indicating that pRBC-EVs can potentially increase the efficacy of several small hydrophobic drugs used for the treatment of malaria.

Liposome-based drug delivery of various anticancer agents of synthetic and natural product origin: apatent overview.

Phospholipid-based liposomal vesicles are among the most effective delivery options currently available for various classes of anticancer drugs. The patents granted to inventions disclosing details on liposomal delivery module by the US Patent and Trademark Office, European Patent Office, and world patent holdings through WIPO (World Intellectual Property Organization) patenting have been sorted based upon liposome, and anticancer keywords within the abstract and claims sections of the patents for the period between 2000 and 2019, thereby disclosing novel liposome formulations encapsulating single, or combination of chemotherapeutic agents that have been far more chemically and physiologically stable, therapeutically efficacious, and comparatively less toxic than their nonliposomal free-drug counterparts. The addedstability, site-specific transport, and payload delivery, enhanced bioavailability, fast body clearance, and biocompatibilitytogether with the controlled and sustained delivery-related benefits claimed in the patentliterature have been exclusively discussed with a focus on the last 5-yearperiod.

Antihepatoma activity of multifunctional polymeric nanoparticles via inhibition of microtubules and tyrosine kinases.

Aim: Synthesis of poly-L-lactic acid nanoparticles comprising of microtubule-inhibitor docetaxel and tyrosine kinase inhibitor sorafenib (PLDS NPs) for hepatoma treatment. Materials & methods: PLDS NPs were prepared by the emulsion solvent evaporation method and the anticancer activity was evaluated in Huh7 hepatoma cells. Results: Real-time imaging of quantum dots incorporating poly-L-lactic acid nanoparticles showed a rapid internalization of the nanoparticles in Huh7 cells. PLDS NPs exerted stronger antiproliferative, apoptotic and antiangiogenic effects than free single drug counterparts. They strongly promoted microtubule bundling, multinucleation and increased mitotic index in Huh7 cells. They also inhibited the expression of pERK1/2, pAKT and cyclin D1. Conclusion: We developed a single-nanoscale platform for dual drug delivery and high-sensitivity quantum dots imaging for hepatoma treatment. [Formula: see text].

CXCR4-targeted liposomal mediated co-delivery of pirfenidone and AMD3100 for the treatment of TGFβ-induced HSC-T6 cells activation.

Background: Liver fibrosis is a chronic liver disease associated with an excessive accumulation of extracellualr matrix (ECM) proteins which ultimately lead to cirrohosis and hepatocellular carcinoma.Purpose: Liver fibrosis therapies that use combination approaches with the ability to affect multiple disease pathways have proven higher efficacies. This study aimed at optimizing and characterizing the co-encapsulation of pirfenidone (PF) and AMD3100 (AMD) into CXCR4-targeted combination liposomes (CTC liposome) for CXCR4 targeting, and the inhibition of major molecular culprits ie α-SMA, CXCR4, TGFβ, and P-p38 involved in liver fibrosis in-vitro.Methods: The CTC liposomes were prepared using the thin-film hydration method. The concentration of encapsulated AMD and PF was measured by HPLC and UV spectrophotometry, respectively. Tramsmission electron microscopy (TEM) was used to determine the liposomal morphology. The CXCR4 targeting ability was determined by CXCR4 redistribution assay. Confocal microscopy and flowcytometry were used to determine the CXCR4 mediated cell uptake. The apoptosis inducing and protein downreguating ability of CTC liposomes were determined by apoptosis assay and western blot analysis, respectively. In-vivo biodistribution and Hoechst staining were used to confirm the feasibility of CTC liposome for the in-vivo applications and drug targeted accumulation, respectively.Results: The TEM studies revealed that CTC liposomes were spherical in shape. The cumulative release of AMD and PF from CTC liposome was 67% and 84%, respectively, at 48 h. Compared to the free drug counterparts, encapsulated drugs displayed higher cell viability. The CXCR4 redistribution assay confirmed the CXCR4 targeting and antagonistic ability of CTC liposomes. The CTC liposomes were internalized more effectively via caveolae-mediated endocytic pathways. CTC liposomes displayed aggressive apoptosis (87.3%) in TGFβ-induced activated HSC-T6 cells suggesting a propensity to fibrosis regression. Also, CTC liposomes significantly reduced α-SMA (65%), CXCR4 (77%), TGFβ (89%), and P-p38 (66%) expressions, better than free drugs. CTC@IR780 liposomes (CTC liposomes incorporating IR780 dye) were more accumulated in fibrotic livers compared to free IR780, as judged by in-vivo imaging, biodistribution analysis, and Hoechst staining. These findings suggest that this simple and stable CTC liposomal system holds a great promise for the treatment and prevention of liver fibrosis.